title: Selective α4β2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons.
abstract: Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.
authors.affiliation: The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Maloku
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kadriu
authors.forename: Adrian
authors.initials: A
authors.lastname: Zhubi
authors.forename: Erbo
authors.initials: E
authors.lastname: Dong
authors.forename: Fabio
authors.initials: F
authors.lastname: Pibiri
authors.forename: Rosalba
authors.initials: R
authors.lastname: Satta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D057890:Epigenomics; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000523:psychology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D000068580:Varenicline; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C104288:A 85380; D001384:Azetidines; D001552:Benzazepines; D051783:Methyl-CpG-Binding Protein 2; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011810:Quinoxalines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005680:gamma-Aminobutyric Acid; D008464:Mecamylamine; D009538:Nicotine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D000068580:Varenicline